21, 21-difluoro pregnenes



United States Patent 22 Claims. 2C1. 260-3973) The present inventionrelates to novel cyclopentanophenanthrene derivatives and process forthe production thereof.

More particularly the invention relates to the novel 21,2l-difiuorocompounds of the pregnane series and more specifically to21,2l-difluoro-A -pregnene-3,ZO-dione which may also contain a doublebond at C 1,2 and/ or C6,7, a chlorine, fluorine or methyl substituentat C6, an u-methyl or fi-methyl group at Cl6, a fi-hydroxy or keto groupat C11 and, in the presence of such substituent at Cll, also a 9a-halosubstituent such as chlorine, bromine or fluorine.

The novel compounds of the present invention are potent agents of theprogestational type and as such exhibit anti-androgenic, anti-estrogenicand anti-gonadotrophic activity in addition to some progestationalactivity.

The novel compounds of the present invention may be illustrated by thefollowing formulae:

CHF2

Orr 6 In. the above equation R has the same meaning as heretofore setforth. R represents hydrogen or carboalkoxy.

In practicing the process above outlined, a 20-keto pregnane is treatedwith an ester such as a dialkyl oxalate or an .alkyl formate in thepresence of a molar equivalent of an alkaline substance such as analkali metal alkoxide, for example, sodium methoxide, or an alkali metalhydride such as sodium hydride in an inert solvent, such as benzene ordioxane to form the sodium salt of the 21-alkoxyoxalyl-ZO-keto-pregnanewhen the ester utilized is-the oxalate, or the sodium salt of2l-hydroxymethylene-20-ketopregnane when the formate ester is utilized.The thus formed salt is suspended in an inert solvent such as ethanol orbenzene to which. another molar equivalent of alkali metal alkoxide isadded and a stream of perchloryl fluoride is then introduced to form the21,2l-difiu0ro-2lalkoxyoxalyl-ZO-keto-pregnane or the21,2l-difluoro-2laldehydo-20-keto-pregnane derivative. By subsequenttreatment of either the last named compounds with a base such as sodiummethoxide or potassium acetate in methanol solution, there is obtainedthe 21,2l-difluoro- 20-keto-pregnane compound.

The novel process of this invention is particularly suitable forpregnanes having a secondary side chain at C-l7. The condensation withthe ester can be'carried out with a A or Amul) compound having ahydroxyl, acyloxy or ethylenedioxy group at C3 and which may contain al6oc or l6B-methyl group; similarly, the condensation can be carried outwith A -3-ketones, and lA -3-ketones, which may also containsubstituents such as methyl, fluorine or chlorine at C6 in either a or,8 steric configuration and/or a methyl substituent at C16 in either aor B steric configuration.

The novel 21,2l-difluoro-pregnanes are stable compounds and can besubjected to further chemical reactions and transformations. Forexample, the introduction of halogen at C6 proceeds smoothly withoutaffecting the 21,21-difluoro moiety.

The following examples serve to illustrate but are not intended to limitthe present invention:

Example 1 A mixture of -10 g. of A -pregnen-3B-ol-20-one, 500 cc. of drybenzene and 1.7 g. of sodium methoxide was treated with 4.6 g. of ethyloxalate and the mixture was stirred for 2 hours at room temperature. Itwas then diluted with 400 cc. of anhydrous ether and the sodium salt ofthe ethyl ester of A -pregnen-3B-ol-2O-one-2l-oxalilic acid wascollected by filtration and suspended in 50 cc. of absolute ethanolcontaining 1.7 g. of sodium methoxide.

A slow stream of perchloryl fluoride was then introduced into the abovesuspension, with continuous stirring, at room temperature, until thereaction no longer showed alkaline reaction. It was then diluted withwater and the 21,2l-difluoro-21-ethoxyoxalyl-A -pregnen-3fi-ol- 20-onewas collected by filtration. It was purified by re,- crystallizationfrom acetone-hexane.

A solution of 7 g. of the above compound in 70 cc. of absolute methanolwas treated with 1 g: of sodium methoxide, under stirring, at roomtemperature and under an atmosphere of nitrogen, for 17 hours. It wasneutralized with glacial acetic acid (1.2 cc.), diluted with water andthe precipitate of the crude 2'1,21-difluoro-A pregnen-3/3-ol-20-o'newas collected by filtration and purified by recrystallization fromacetone-hexane.

Alternatively, this hydrolysis was carried out by refluxing a solutionof 0.5 g. of 21,21-difluoro-21-ethoxyoxalyl- A -pregnene-3-;8-ol-20-oneand l g. of potassium acetate in 40 cc. of methanol for 5 hours. Byprecipitation in Water, conventional isolation and chromatography onalumina, there was obtained 21,2l-difluoro-M-pregnene- -3fi-ol-20-onewas collected by 3 3 p-ol-20-one, identical with the one obtained inaccordance with the preceding paragraph.

5 g. of the above compound was dissolved in 140 cc. of xylene and 5 cc.of cyclohexanone, 25 cc. was distilled in order to remove traces ofmoisture, g. of aluminum isopropoxide dissolved in 25 cc. of anhydrousxylene was added in the course of 5 minutes, and the distillation wascontinued for 40 minutes. Water and ice were added to the cooled mixtureand the volatile solvents were removed by steam distillation. The solidwas collected by filtration and recrystallized from acetone-hexane, thusyielding 21,2l-difluoro-progesterone.

Example 2 A mixture of 1 g. of 21,21-difluoro-progesterone prepared inaccordance with Example 1, 50 cc. of t-butanol, 0,4 g. of recentlysublimed selenium dioxide and 0.2 cc. of pyridine was refluxed under anatmosphere of nitrogen for 48 hours, filtered through celite and thesolvent was evaporated under reduced pressure. The residue was refluxedwith decolorizing charcoal in acetone for one hour, filtered and theacetone was evaporated; the crude product was purified by chromatographyon neutral alumina, thus yielding 21,21difluoro-A -pregnadiene-3,20-dione.

' Example 3 A mixture of 1 g. of 21,21-difluoro-progesterone prepared inaccordance with Example 1, g. of chloranil, 75 cc. of ethyl acetate and25 cc. of acetic acid was refluxed under an atmosphere of nitrogen for96 hours. The mixture was cooled, washed with 10% aqueous sodiumhydroxide solution until the washings were. colorless, then with water,dried over anhydrous sodium sulfate and the solvent was evaporated. Bychromatography of the residue on neutral alumina, there was obtained 21,21difluoro-A -pregnadiene-S,20-dione.

1.0 g. of the above compound was refluxed with selenium dioxide int-butanol and in the presence of pyridine, following the reactionconditions and procedure of isolation of Example 2, thus yielding21,21-difluoro- A -pregnatriene-3,20-dione.

Example 4 Q A mixture of 1.0 g. of 21,21-difluoro-A -pregnadiene-3,20-dione, obtained in accordance with the method of Example 2, wastreated with chloranil according to the method of Example 3 to thusobtain 21,21-difluoro-A pregnatriene-3,20-dione, identical with the oneobtained in accordance with the method of Example 3.

Example 5 A mixture of 10 g. of A -pregnen-3fl-ol-20-one, 500 cc. of drybenzene and 1.7 g. of sodium methoxide was treated with 4.4 g. of ethylformate and the mixture was stirred for 2 hours at room temperature. Itwas then diluted with 400 cc. of anhydrous ether and the sodium salt ofthe 21-hydroxymethylene-A -pregnen-3,B-ol-20- one was collected byfiltration and suspended in 50 cc. of absolute ethanol containing 1.7 g.of sodium methoxide.

A slow stream of perchloryl fluoride was then introduced into the abovesuspension, with continuous stirring, at room temperature, until thereaction no longer showed alkaline reaction. It was then diluted withwater and the 21,2l-difiuoro-21-aldehydro-A -pregnen-3fi-ol-2O-one wascollected by filtration. It was purified by recrystallization fromacetone-hexane.

A solution of 7 g. of the above compound in 70 cc. of absolute methanolwas treated with 1 g. of sodium methoxide, under stirring, at roomtemperature and under an atmosphere of nitrogen for 17 hours.

It was neutralized with glacial acetic acid (1.2 cc.), diluted withwater and Alternatively, this hydrolysis was carried out by refluxing asolution of 0.5 g. of 21,21-difluoro-21-aldehydo- A-pregnen-3B-ol-2O-one and 1 g. of potassium acetate in 40 cc. ofmethanol for 5 hours. By precipitation in water, conventional isolationand chromatography on,

alumina, there was obtained 21,21-difluoro-A -pregnen- 3fi-ol-20-one,identical with the one obtained in accordance with the precedingparagraph and with Example 1.

Example 6 A mixture of 5.0 g. of A pregnadiene-3,20-dione, 300 cc. ofdry benzene and 1.0 g. of sodium methoxide was treated with 2.5 g. ofethyl oxalate and the mixture was stirred at room temperature for 2hours. The mixture was diluted with 200 cc. of anhydrous ether and thesodium salt of the ethyl ester of A -pregnadiene-3,20- dione-21-oxalilicacid was collected by filtration and suspended in 30 cc. of absoluteethanol containing 1.0 g. of sodium methoxide.

A slow stream of perchloryl fluoride was then introduced into thesuspension with continuous stirring at room temperature until thereaction no longer showed alkaline reaction. It was then diluted withwater and 21,21 difluoro 21 ethoxyoxalyl A pregnadiene- 3,20-dione wascollected by filtration. It was purified by recrystallization fromacetone-hexane.

A solution of 3.8 g. of the above compound in cc. of absolute methanolwas treated with 0.7 g. of sodium methoxide, under stirring, at roomtemperature and under an atmosphere of nitrogen for 17 hours. It wasneutralized with glacial acetic acid (0.7 cc.), diluted with water andthe precipitate of the crude 21,21-difluoro-A pregnadiene-3,20-dione wascollected by filtration and purified by recrystallization fromacetone-hexane.

The hydrolysis was also carried out by refluxing a solution of 0.5 g.21,21-difluor0-21-ethoxyoxalyl-A -pregnadi ene-3,20-dione and 1.0 g. ofpotassium acetate in 40 cc. of methanol for 5 hours. By precipitation inwater, conventional isolation and chromatography on alumina, there wasobtained 21,2l-difluoro-A -pregnadiene-3,20-dione, identical with theone obtained above.

Example 7 By following the procedure of Example 6, A pregnatr-iene 3,20dione gave 21,21 difluoro-A pregnatriene-3,20-dione, identical with theone obtained in accordance with the methods of Example 3 and Ex- I ample4.

the precipitate of the crude 21,21-difluoro-A -pregnenfiltration andpurified by recrystallization from acetone-hexane.

Example 8 By following the procedure of Example 1, 16a-methyl- A-pregnen-3B-ol-2O-one gave 21,21-difiuoro-16u-methyl- A-pregnen-3fi-ol-20-one and 21,21-difluoro-l6x-methyl- A-pregnene-3,20-dione.

Example 9 By following the procedure of Examples 2, 3, and 4, 21,21difluoro 16m methyl A pregnene 3,20- dione obtained in Example 8 wasconverted into 21,21- difluoro 16oz methyl A pregnadiene 3,20 dione,21,21 difluoro 16cc methyl A pregnadiene 3,20- dione and 21,21 difluoro16a. methyl A pregnatriene-3,20-dione.

Example 10 By following the procedure of Examples 1, 2, 3, and 4,16fl-methyl-A pregnen-3fl-ol-20-one was converted into 21,21 difluoro1618 methyl A pregnen 318 ol 20- one; 21,21 difluoro 16B methyl Apregnene 3,20- dione; 21,21 difluoro 1613 methyl A pregnadiene- 3,20dione; 21,21 difluoro 16B methyl A pregnadiene 3,20 dione; and 21,21difluoro 16B methyl- A -pregnatriene-3,20-dione.

Example 11 5.0 g. of 21,2l-difluoro-progesterone, obtained in Example 1,in 50 cc. of dioxane was treated with 6 cc. of ethyl orthoformate and180 mg. of p-toluenesulfonic acid and the mixture was stirred at roomtemperature for 40 minutes; there was then added 15 cc. of pyridine,followed by the slow addition, under stirring, of 600 cc. of water. Thereaction product was extracted with ether and the extract was washedwith water, dried over anhydrous sodium sulfate and evaporated todryness. Crystallization of the residue from acetone-hexane yielded 2l,21difluoro-3-ethoxy-A -pregnadien-20-one.

A mixture of 5 g. of the above compound, 100 cc. of acetone, 20 cc. ofWater and 2cc. of sodium acetate was cooled to C. and treated with 1.8g. of N-chlorosuccinimide followed by 2 cc. of glacial acetic acid; themixture was stirred at 0 C. for 1 hour and then poured into water; theprecipitate formed was collected by filtration, washed with water, driedand recrystallized from acetonehexane. There was thus obtained6fi-chloro-21,21-difluoro-A -pregnene-3,20-dione. In order to invert thesteric configuration at C-6, a slow stream of dry hydrogen chloride wasintroduced for one hour into a solution of the latter compound in 100cc. of glacial acetic acid, at a temperature of around 15 C., themixture was then poured into water, the precipitate was collected,washed with water, dried and recrystallized from acetone-hexane. Theresulting 6achloro-21,21-difluoro-A -pregnene-3,20- dione was refluxedwith selenium dioxide in mixture with t-butanol, in the presence ofpyridine, and under an atmosphere of nitrogen, in accordance with theprocedure described in Example 2. There was thus obtained6achloro-21,21difluoro-A -pregnadiene-3,20-dione.

The latter compound was treated with chloranil in accordance with themethod of Example 3 to afford .6- chloro-21,21-difluoro-A-pregnatriene-3,2O-dione.

The 60c chloro 21,21-difluoro-A -pregnene-3,20-dione was refluxed withchloranil in mixture with ethyl acetate and acetic acid in accordancewith the method of Example 3; there was thus obtained6-chloro-2l,21-difluoro- A -pregnadiene-ii,20-dione.

Example 12 In accordance with the method described in Example 1, g. ofthe acetate of A pregnadien-3B-ol-20-one was converted successively intothe sodium salt of the ethyl ester of A-pregnadien-3fi-ol-ZO-one-Z1-oxalilic acid,21,2l-difluoro-Zlethoxyoxalyl A5901) pregnadien 3eol-20-one,21,21-difiuoro-A -pregnadien-3fi-ol-20-one and 21,21-difluoro-A-pregnadiene-3,20-dione.

The starting material, namely, A -pregnadien-3B- ol-20-one 3-acetate wasobtained by partial hydrogenation of A -pregnatrien-3 S-ol-ZO-oneacetate, described in our copending patent application Serial No.860,734 filed on December 21, 1959, now abandoned, in accordance withthe method described by Djerassi et al. in J. Org. Chem. 16, 1278(1951).

Example 13 To a solution of 2.85 g. of 21,21-difluoro-Apregnadiene-3,20-dione in 45 cc. of methylene chloride and 76 cc. ofdioxane, was added 6.6 cc. of a 1% aqueous solution of perchloric acidand 1.23 g. of N-bromoacetamide and the mixture was stirred at roomtemperature for 20 minutes. 1.23 g. of sodium sulfite in 66 cc. of waterand the mixture was concentrated to one third of its volume underreduced pressure. The residue was diluted with water and the precipitatewas collected by filtration, washed with water, dried and recrystallizedfrom acetone=hexane, thus furnishing 90cbromo-21,2l-difluoro-M-pregnene-l113-01- 3,20-diene.

Under vigorous stirring there was then added A mixture of 1.6 g. of theabove compounded, 1.9 g. of recently fused potassium acetate and cc. ofacetone was refluxed for 18 hours, most of the acetone was removed bydistillation, the residue was diluted with water and the precipitate wascollected, washed with water, dried and recrystallized from acetone,thus yielding 2l,2ldifluoro-9 5,1 1[3-oxido-A -pregnene-3,20-dione.

A solution of 600 mg. of the above compound in 20 cc. of methylenechloride was added at -80 C. and with vigorous stirring to a solution of1.1 g. of anhydrous hydrogen fluoride in 1.95 g. of tetrahydrofuran,over a period of 5 minutes. The mixture was kept for 10 minutes furtherat 80 C., then at 0 C. for 7 hours and poured into water containing anexcess of sodium bicarbonate. The product was treated with methylenechloride and the extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. Chromatography of the residueon neutral alumina afforded 9a,2l,2l-trifluoro-A-pregnen-l1/8-ol-3,20-dione.

A solution of 500 mg. of the above compound in 20 cc. of glacial aceticacid was treated dropwise under stirring with a solution of 125 mg. ofchromium trioxide dissolved in 5 cc. of 50% acetic acid, taking carethat the temperature remained below 15 C. It was allowed to stand atroom temperature for 1 hour, poured into ice water and the precipitatewas collected, washed with water, dried and recrystallized fromacetone-ether, thus affording 9a,21,21-trifluoro-A-pregnene-3,11,20-trione.

In accordance with the method of Examples 2 and 3, the latter compoundwas converted into 9a,21,21-trifluoro-A -pregnadiene6,1 1,20-trione,9a,21,21-trifluoro- A pregnadiene-3,l1,20-trione and 9a,21-21 trifluoro-A -pregnatriene-3 ,1 1,20-trione.

Example 14 A solution of 400 mg. of 21,21-difluoro-9B-1lfi-oxido- A-pregnene-3,20-dione, produced as described in the preceding example, in4 cc. of redistilled chloroform was mixed with 3.3 cc. of a chloroformsolution containing 1.5 molar equivalents of dry hydrogen chloride, withstirring and in the course of 35 minutes, maintaining the temperaturearound 0 C. The mixture was kept for one additional hour at 0 C., andthen diluted with water; the chloroform layer was separated, washed withaqueous sodium bicarbonate solution and water, dried over anhydroussodium sulfate and the chloroform was evaporated. Recrystallization ofthe residue from acetone afforded 9u-chloro-21.,21,difluor0-A-pregnen-11,6-01- 3,20-dione.

By following the procedures of Examples 2, 3 and 4, the above compoundwas converted into 9a-chloro-21,21- difluoro-A-pregnadien-1l,8-ol-3,20-dione, 9a-chloro-21, 21 difluoro- Apregnadien-l lB-ol-3,20-dione and chloro-21,21difiuoro-A -pregnatrien-llfi-ol-3 ,20-dione.

Example 15 In accordance with the methods of Examples 2, 3, and t 4,-9a,21,2l trifluoro A pregnen-l1;S-ol-3,20-dione obtained as described inExample 13, was converted into Example 16 In accordance with the methodof Example 1, 60- methyl-A -pregnadiene-3,20-dione, described in BelgiumPatent No. 576,345, was treated with ethyl oxalate in benzene solutionand in the presence of sodium methoxide to produce the sodium salt ofthe ethyl ester of 60a methyl A -pregnadiene-3,20-dione-21-oxalilicacid; treatment with perchloryl fluoride gave 6a-methyl-21,21- difluoro2l ethoxyoxalyl A pregnadiene 3,20- dione. Hydrolysis of the abovecompound with potassium acetate in methanol solution afiorded finally6amethyl-Z 1 ,2 1difluoro-A -pregnadiene-3 ,20-dione.

I Example 17 By following the procedure of the previous example butusing 6-methyl-A -pregnatriene-3,20-dione (described in Belgium PatentNo. $76,345) as starting material, there was obtained6-methyl-21,21-difiuoro-A pregnatriene-3,20-dione.

Example 18 In accordance with the method of Example 17, 5 g. of6a-fluoro-l-dehydro-progesterone, was converted successively into thesodium salt of the ethyl ester of 6afluoro-A -pregnadiene-3,20-dione21-oxalilic acid, 60c, 21,21 trifluoro 21 ethoxyoxalyl A pregnadiene-3,20-dione and finally into 6a,21,21-trifluoro-A-pregnadiene-3,20-dione.

Treatment of the above compound with chloranil in mixture of ethylacetate andacetic acid, in accordance with the procedure of Example 3,gave 6,21,21-trifiuoro- A -pregnatriene-3,ZO-dione.

The starting material, 6a-fiuoro-1-dehydro-progesterone was obtained byselenium dioxide oxidation of 60afluoro-progesterone, described byBowers et al. in Tetrahedron 1958, vol. 3, pp. 14-27.

Example 19 By following the procedure of Example 11, 2 g. of 21,21-difluoro-l6a-methyl-A -pregnene 3,20-dione obtained as described inExample 9, was converted into 6/8-chloro- 21,21, difluoro-lfia-methyl Apregnene-3,20-dione and then into 60c chloro 21,21 difluoro 16a methyl Apregnene-3,20-dione. Upon treatment with selenium dioxide in t-butanol,in accordance with the method of Example 2, there was obtained6u-chloro-21,21-difiuoro- 16oz methyl A pregnadiene-3,20-dione. Upontreatment of the latter compound with chloranil as described in Example3, there was obtained 6-chloro-21,21-difiuoro- 16ot-methyl-A-pregnatriene-3,20-dione.

By following the procedure of Example 3, 6oc-Chl010- 21,21difluoro-16a-methyl A pregnene-3,20-dione was converted into the6-chl0ro-2l,21-difiuoro-16oa-methyl- A -pregnadiene-3,20-dione.

Example 20 By substituting in the preceding Example, 16fi-methyl-21,21-difluoro-A -pregnene-3,2O dione (obtained in accordance with themethod of Example there was obtained 60: chloro 21,21 difluoro 16Bmethyl A pregnene-3,20-dione, 6u-chl0ro-21,21-difiuoro-16,8-methyl A-pregnadiene-3,20-dione, 6-chloro-21,21-difluoro-16flmethyl-A-pregnadiene-3,20-dione and 6-chloro-21,21- difluoro-16,8-methyl-A-pregnatriene-3,20-dione.

Example 21 A slow stream of perchloryl fluoride was introduced for 1hour, into a suspension of 10 g. of the sodium salt of the ethyl esterof A -pregnen-3/3-ol-20-one-2l-oxalilic acid in 200 cc. of anhydrousbenzene. Air was then passed through the solution for 10 minutes andthen 1.7 g. of sodium methoxide in 50 cc. of methanol was added. Thereaction mixture was treated again with perchloryl fluoride for 1 hourmore, diluted water, and the 21,21- difluoro 21 ethoxyoxalyl A-pregnen-3fl-ol-20-one collected by filtration.

We claim:

1. A method for the production of a 21,21-difluoro- ZO-keto-steroid ofthe pregnane series which comprises reacting a21-hydroxymethylene-ZO-keto-pregnane with perchloryl fluoride to formthe corresponding 21,21- difiuoro-Z1-aldehydo-20-keto-pregnane andhydrolyzing with a base to form .the corresponding 21,21-difluoro--keto-pregnane.

2. A compound of .the following formula:

CHFz

wherein R is selected from the group consisting of a-methyl andfi-methyl; Z is selected from the group consisting of a double bondbetween 0-1 and C2 and a saturated linkage between 0-1 and C2; and Z isselected from the group consisting of a double bond between C6 and C7and a saturated linkage between C6 and C-7 with at least one Z and Zbeing a double bond.

3. 16 methyl 21,21 difluoro A pregnadiene- 3,20dione.

4. 16 methyl 21,21 difluoro A pregnadiene- 3,20-dione.

5. a methyl 21,21 difluoro A pregnatriene- 3,20-dione.

6. methyl 21,21 difluoro A pregnatriene- 3,20-dione.

7. A compound of the following formula:

CHF2

wherein R is selected from the group consisting of hydrogen, a-methyland B-methyl; Z is selected from the group consisting of a double bondbetween 0-1 and C2 and a saturated linkage between C1 and C2; and Z' isselected from the group consisting of a double bond between C6 and C7and a saturated linkage between C6 and C7.

8. 6oz chloro 21,21 difluoro A pregnene 3,20- dione.

9.6a chloro 21,21 difluoro A pregnadiene- 3,20-dione.

10. 6 chloro 21,21 difluoro A pregnadiene- 3,20-dione.

11. 16 methyl 6a chloro 21,21 difluoro A pregnene-3,20-dione.

12. A compound of the following formula:

CHFz

wherein R is selected from the group consisting of methyl and fluorine.

13. 6oc,21,2I{rifluorm -pregnadiene-3,2O-dione.

14. A compound of the following formula:

GHF:

wherein R is selected from the group consisting of methyl wherein X isselected from the group consisting of chlorine, bromine and fluorine; Yis selected from the group consisting of fi-hydroxy and keto; Z isselected from the group consisting of a double bond between C-1 and C-2and a saturated linkage between C-1 and C-2; and Z is selected from thegroup consisting of a double bond between C-6 and C-7 and a saturatedlinkage between C-6 and C-7.

19. 90:,21,2l-trifluoro-A -pregnen-l1,3-01-3,20-dione.

20. 9a,21,21-trifluoro-A -pregnadiene-3,11,20-trione.

21. 9a,21,21 trifluoro A -pregnadien 11,8 ol- 3,20-di0ne.

22. 9a,21,21 trifluoro A pregnatriene 3,11,20- trione.

References Cited by the Examiner UNITED STATES PATENTS 2,837,464 6/1958Nobile 19551 2,882,282 4/1959 Agnello et a1 260397.3 2,953,581 9/1960Jensen 260397.3 2,965,654 12/1960 Bergstrom 260-3973 OTHER REFERENCESNakanishi et al., I.A.C.S., vol. 81, 1959, pp. 5259-60. Ringold et al.,J.A.C.S., vol. 80, 1958, p. 6464.

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, MORRIS LIEBMAN, Examiners.

2. A COMPOUND OF THE FOLLOWING FORMULA: